IL6_RAT
ID IL6_RAT Reviewed; 211 AA.
AC P20607;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Interleukin-6 {ECO:0000305};
DE Short=IL-6;
DE Flags: Precursor;
GN Name=Il6 {ECO:0000312|RGD:2901}; Synonyms=Il-6;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2789217; DOI=10.1016/s0021-9258(18)71589-5;
RA Northemann W., Braciak T.A., Hattori M., Lee F., Fey G.H.;
RT "Structure of the rat interleukin 6 gene and its expression in macrophage-
RT derived cells.";
RL J. Biol. Chem. 264:16072-16082(1989).
RN [2]
RP SUBCELLULAR LOCATION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE AND IL1B.
RX PubMed=23955712; DOI=10.1038/nm.3265;
RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J.,
RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P.,
RA Kunos G.;
RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by
RT endocannabinoids mediates beta cell loss in type 2 diabetes.";
RL Nat. Med. 19:1132-1140(2013).
CC -!- FUNCTION: Cytokine with a wide variety of biological functions in
CC immunity, tissue regeneration, and metabolism. Binds to IL6R, then the
CC complex associates to the signaling subunit IL6ST/gp130 to trigger the
CC intracellular IL6-signaling pathway. The interaction with the membrane-
CC bound IL6R and IL6ST stimulates 'classic signaling', whereas the
CC binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'.
CC Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R
CC complexes on transmitter cells activate IL6ST receptors on neighboring
CC receiver cells. {ECO:0000250|UniProtKB:P08505}.
CC -!- FUNCTION: IL6 is a potent inducer of the acute phase response. Rapid
CC production of IL6 contributes to host defense during infection and
CC tissue injury, but excessive IL6 synthesis is involved in disease
CC pathology. In the innate immune response, is synthesized by myeloid
CC cells, such as macrophages and dendritic cells, upon recognition of
CC pathogens through toll-like receptors (TLRs) at the site of infection
CC or tissue injury. In the adaptive immune response, is required for the
CC differentiation of B-cells into immunoglolin-secreting cells. Plays a
CC major role in the differentiation of CD4(+) T cell subsets. Essential
CC factor for the development of T follicular helper (Tfh) cells that are
CC required for the induction of germinal-center formation. Together with
CC IL21, controls the early generation of Tfh cells and are critical for
CC an effective antibody response to acute viral infection. Required to
CC drive naive CD4(+) T cells to the Th17 lineage, through 'cluster
CC signaling' by dendritic cells. Also required for proliferation of
CC myeloma cells and the survival of plasmablast cells.
CC {ECO:0000250|UniProtKB:P08505}.
CC -!- FUNCTION: Acts as an essential factor in bone homeostasis and on
CC vessels directly or indirectly by induction of VEGF, resulting in
CC increased angiogenesis activity and vascular permeability. Induces,
CC through 'trans-signaling' and synergistically with IL1B and TNF, the
CC production of VEGF. Involved in metabolic controls, is discharged into
CC the bloodstream after muscle contraction increasing lipolysis and
CC improving insulin resistance. 'Trans-signaling' in central nervous
CC system regulates energy and glucose homeostasis. Mediates, through GLP-
CC 1, crosstalk between insulin-sensitive tissues, intestinal L cells and
CC pancreatic islets to adapt to changes in insulin demand (By
CC similarity). Also acts as a myokine (By similarity). Plays a protective
CC role during liver injury, being required for maintenance of tissue
CC regeneration. Also has a pivotal role in iron metabolism by regulating
CC HAMP/hepcidin expression upon inflammation or bacterial infection.
CC Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation-
CC induced epithelial regeneration (By similarity).
CC {ECO:0000250|UniProtKB:P05231, ECO:0000250|UniProtKB:P08505}.
CC -!- SUBUNIT: Component of a hexamer of two molecules each of IL6, IL6R and
CC IL6ST; first binds to IL6R to associate with the signaling subunit
CC IL6ST. Interacts with IL6R (via the N-terminal ectodomain); this
CC interaction may be affected by IL6R-binding with SORL1, hence
CC decreasing IL6 cis signaling. Interacts with SORL1 (via the N-terminal
CC ectodomain); this interaction leads to IL6 internalization and
CC lysosomal degradation. May form a trimeric complex with the soluble
CC SORL1 ectodomain and soluble IL6R receptor; this interaction might
CC stabilize circulating IL6, hence promoting IL6 trans signaling.
CC {ECO:0000250|UniProtKB:P08505}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23955712}.
CC -!- INDUCTION: In pancreatic islets, secretion is stimulated by IL1B. In
CC islets from Zucker diabetic fatty (ZDF) rats, but not lean animals,
CC secretion is also increased by endocannabinoid anandamide/AEA.
CC {ECO:0000269|PubMed:23955712}.
CC -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}.
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DR EMBL; M26744; AAA77659.1; -; mRNA.
DR EMBL; M26745; AAA41430.1; -; Genomic_DNA.
DR PIR; A34247; A34247.
DR RefSeq; NP_036721.1; NM_012589.2.
DR AlphaFoldDB; P20607; -.
DR SMR; P20607; -.
DR STRING; 10116.ENSRNOP00000013732; -.
DR PhosphoSitePlus; P20607; -.
DR PaxDb; P20607; -.
DR Ensembl; ENSRNOT00000013732; ENSRNOP00000013732; ENSRNOG00000010278.
DR GeneID; 24498; -.
DR KEGG; rno:24498; -.
DR UCSC; RGD:2901; rat.
DR CTD; 3569; -.
DR RGD; 2901; Il6.
DR eggNOG; ENOG502S7Q4; Eukaryota.
DR GeneTree; ENSGT00390000000878; -.
DR HOGENOM; CLU_096521_0_0_1; -.
DR InParanoid; P20607; -.
DR OMA; ENAKAMQ; -.
DR OrthoDB; 1144279at2759; -.
DR PhylomeDB; P20607; -.
DR Reactome; R-RNO-1059683; Interleukin-6 signaling.
DR Reactome; R-RNO-110056; MAPK3 (ERK1) activation.
DR Reactome; R-RNO-112411; MAPK1 (ERK2) activation.
DR Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-RNO-8957275; Post-translational protein phosphorylation.
DR PRO; PR:P20607; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000010278; Expressed in spleen and 5 other tissues.
DR Genevisible; P20607; RN.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0005896; C:interleukin-6 receptor complex; ISS:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IDA:RGD.
DR GO; GO:0008083; F:growth factor activity; ISO:RGD.
DR GO; GO:0005138; F:interleukin-6 receptor binding; IDA:RGD.
DR GO; GO:0005102; F:signaling receptor binding; IDA:RGD.
DR GO; GO:0002526; P:acute inflammatory response; IEP:RGD.
DR GO; GO:0006953; P:acute-phase response; IEA:UniProtKB-KW.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0046849; P:bone remodeling; IEP:RGD.
DR GO; GO:0060445; P:branching involved in salivary gland morphogenesis; ISO:RGD.
DR GO; GO:0045454; P:cell redox homeostasis; IMP:RGD.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; IEP:RGD.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEP:RGD.
DR GO; GO:0071392; P:cellular response to estradiol stimulus; IEP:RGD.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; ISO:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEP:RGD.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD.
DR GO; GO:0097398; P:cellular response to interleukin-17; ISO:RGD.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0031669; P:cellular response to nutrient levels; IEP:RGD.
DR GO; GO:1990646; P:cellular response to prolactin; IEP:RGD.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:RGD.
DR GO; GO:0098586; P:cellular response to virus; ISS:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD.
DR GO; GO:0042832; P:defense response to protozoan; ISO:RGD.
DR GO; GO:0051607; P:defense response to virus; ISO:RGD.
DR GO; GO:0031018; P:endocrine pancreas development; ISO:RGD.
DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; ISO:RGD.
DR GO; GO:0010467; P:gene expression; ISO:RGD.
DR GO; GO:0002314; P:germinal center B cell differentiation; ISS:UniProtKB.
DR GO; GO:0070091; P:glucagon secretion; ISO:RGD.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0002384; P:hepatic immune response; ISO:RGD.
DR GO; GO:0072574; P:hepatocyte proliferation; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; ISO:RGD.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0097421; P:liver regeneration; ISS:UniProtKB.
DR GO; GO:0031294; P:lymphocyte costimulation; IEP:RGD.
DR GO; GO:0046716; P:muscle cell cellular homeostasis; ISO:RGD.
DR GO; GO:0002262; P:myeloid cell homeostasis; ISO:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR GO; GO:0045779; P:negative regulation of bone resorption; ISO:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0032682; P:negative regulation of chemokine production; ISO:RGD.
DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; ISO:RGD.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:RGD.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IDA:RGD.
DR GO; GO:0046888; P:negative regulation of hormone secretion; ISO:RGD.
DR GO; GO:2000660; P:negative regulation of interleukin-1-mediated signaling pathway; ISO:RGD.
DR GO; GO:0045837; P:negative regulation of membrane potential; IMP:RGD.
DR GO; GO:0048635; P:negative regulation of muscle organ development; IDA:RGD.
DR GO; GO:1901215; P:negative regulation of neuron death; IDA:RGD.
DR GO; GO:2000635; P:negative regulation of primary miRNA processing; ISO:RGD.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:RGD.
DR GO; GO:0031175; P:neuron projection development; ISO:RGD.
DR GO; GO:0001781; P:neutrophil apoptotic process; ISO:RGD.
DR GO; GO:0002675; P:positive regulation of acute inflammatory response; ISO:RGD.
DR GO; GO:1902512; P:positive regulation of apoptotic DNA fragmentation; ISO:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:RGD.
DR GO; GO:0050871; P:positive regulation of B cell activation; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0071864; P:positive regulation of cell proliferation in bone marrow; ISO:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISO:RGD.
DR GO; GO:0045740; P:positive regulation of DNA replication; IMP:RGD.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:RGD.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:RGD.
DR GO; GO:0090091; P:positive regulation of extracellular matrix disassembly; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ARUK-UCL.
DR GO; GO:0060252; P:positive regulation of glial cell proliferation; ISO:RGD.
DR GO; GO:0014015; P:positive regulation of gliogenesis; ISO:RGD.
DR GO; GO:0002639; P:positive regulation of immunoglobulin production; ISS:UniProtKB.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:RGD.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISO:RGD.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISO:RGD.
DR GO; GO:0032745; P:positive regulation of interleukin-21 production; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISO:RGD.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISO:RGD.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:RGD.
DR GO; GO:1903800; P:positive regulation of miRNA maturation; ISO:RGD.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IMP:RGD.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:RGD.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; ISO:RGD.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:RGD.
DR GO; GO:1901731; P:positive regulation of platelet aggregation; ISO:RGD.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IDA:RGD.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IDA:RGD.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IDA:RGD.
DR GO; GO:1904894; P:positive regulation of receptor signaling pathway via STAT; ISO:RGD.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:RGD.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISO:RGD.
DR GO; GO:2000553; P:positive regulation of T-helper 2 cell cytokine production; ISO:RGD.
DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0045727; P:positive regulation of translation; ISO:RGD.
DR GO; GO:0051971; P:positive regulation of transmission of nerve impulse; IDA:RGD.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:RGD.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:RGD.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0008360; P:regulation of cell shape; IDA:RGD.
DR GO; GO:0045188; P:regulation of circadian sleep/wake cycle, non-REM sleep; IMP:RGD.
DR GO; GO:0070092; P:regulation of glucagon secretion; ISS:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0010574; P:regulation of vascular endothelial growth factor production; ISO:RGD.
DR GO; GO:0014823; P:response to activity; ISS:UniProtKB.
DR GO; GO:0043200; P:response to amino acid; IEP:RGD.
DR GO; GO:0046677; P:response to antibiotic; IEP:RGD.
DR GO; GO:0010996; P:response to auditory stimulus; IEP:RGD.
DR GO; GO:0009617; P:response to bacterium; IEP:RGD.
DR GO; GO:0031000; P:response to caffeine; IEP:RGD.
DR GO; GO:0051592; P:response to calcium ion; IEP:RGD.
DR GO; GO:0009409; P:response to cold; IEP:RGD.
DR GO; GO:0034097; P:response to cytokine; IEP:RGD.
DR GO; GO:0051602; P:response to electrical stimulus; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; ISO:RGD.
DR GO; GO:0140459; P:response to Gram-positive bacterium; IEP:RGD.
DR GO; GO:0009408; P:response to heat; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0009612; P:response to mechanical stimulus; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR GO; GO:0009611; P:response to wounding; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0001878; P:response to yeast; IEP:RGD.
DR GO; GO:0042110; P:T cell activation; ISO:RGD.
DR GO; GO:0061470; P:T follicular helper cell differentiation; ISS:UniProtKB.
DR GO; GO:0072540; P:T-helper 17 cell lineage commitment; ISS:UniProtKB.
DR GO; GO:0010573; P:vascular endothelial growth factor production; ISS:UniProtKB.
DR GO; GO:0042060; P:wound healing; IEP:RGD.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR003574; IL-6.
DR InterPro; IPR030474; IL-6/GCSF/MGF.
DR InterPro; IPR030473; IL6/GCSF/MGF_CS.
DR PANTHER; PTHR10511; PTHR10511; 1.
DR PANTHER; PTHR10511:SF3; PTHR10511:SF3; 1.
DR Pfam; PF00489; IL6; 1.
DR PIRSF; PIRSF001935; IL6_MGF_GCSF; 1.
DR PRINTS; PR00433; IL6GCSFMGF.
DR SMART; SM00126; IL6; 1.
DR SUPFAM; SSF47266; SSF47266; 1.
DR PROSITE; PS00254; INTERLEUKIN_6; 1.
PE 2: Evidence at transcript level;
KW Acute phase; Cytokine; Disulfide bond; Growth factor; Phosphoprotein;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..211
FT /note="Interleukin-6"
FT /id="PRO_0000015593"
FT MOD_RES 79
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P05231"
FT DISULFID 70..76
FT /evidence="ECO:0000250|UniProtKB:P05231"
FT DISULFID 99..109
FT /evidence="ECO:0000250|UniProtKB:P05231"
SQ SEQUENCE 211 AA; 24357 MW; 17D248A14F96B5C1 CRC64;
MKFLSARDFQ PVAFLGLMLL TATAFPTSQV RRGDFTEDTT HNRPVYTTSQ VGGLITYVLR
EILEMRKELC NGNSDCMNSD DALSENNLKL PEIQRNDGCF QTGYNQEICL LKICSGLLEF
RFYLEFVKNN LQDNKKDKAR VIQSNTETLV HIFKQEIKDS YKIVLPTPTS NALLMEKLES
QKEWLRTKTI QLILKALEEF LKVTMRSTRQ T
